Isoquinolinone potassium channel inhibitors

ABSTRACT

The present invention relates to compounds having the structure (I) useful as potassium channel inhibitors to treat cardiac arrhythmias, and the like.

CROSS REFERENCE TO RELATED APPLICATION

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/US2004/030484, filed Sep. 17, 2004,which claims priority under 35 U.S.C. §119(e) from U.S. ProvisionalApplication Ser. No. 60/505,215, filed Sep. 23, 2003.

BACKGROUND OF THE INVENTION

The present invention relates broadly to compounds that are useful aspotassium channel inhibitors. Compounds in this class may be useful asKv1.5 antagonists for treating and preventing cardiac arrhythmias, andthe like, and as Kv1.3 inhibitors for treatment of immunosuppression,autoimmune diseases, and the like.

Voltage gated potassium channels (Kv) are multimeric membrane proteinscomposed of four α subunits and are often associated with accessory βsubunits. Kv channels are typically closed at resting membranepotentials, but open upon membrane depolarization. They are involved inthe repolarization of the action potential and thus in the electricalexcitability of nerve and muscle fibers. The Kv1 class of potassiumchannels is comprised of at least seven family members, named Kv1.1,Kv1.3, Kv1.5, etc. Functional voltage-gated K⁺ channels may exist eitheras homo-oligomers composed of identical subunits, or hetero-oligomers ofdifferent subunit composition. This phenomenon is thought to account forthe wide diversity of K⁺ channels. However, subunit compositions ofnative K⁺ channels and the physiologic role that particular channelsplay are, in most cases, still unclear.

The Kv1.3 voltage-gated potassium channel is found in neurons, bloodcells, osteoclasts and T-lymphocytes. Membrane depolarization by Kv1.3inhibition has been shown to be an effective method to prevent T-cellproliferation and therefore has applications in many autoimmuneconditions. Inhibition of K⁺ channels in the plasma membrane of humanT-lymphocytes has been postulated to play a role in elicitingimmunosuppressive responses by regulating intracellular Ca⁺⁺homeostasis, which has been found to be important in T-cell activation.Blockade of the Kv1.3 channel has been proposed as a novel mechanism foreliciting an immunosuppressant response (Chandy et al., J. Exp. Med.160: 369, 1984; Decoursey et al., Nature, 307: 465, 1984). However, theK⁺ channel blockers employed in these early studies were non-selective.In later studies, Margatoxin, which blocks only Kv1.3 in T-cells, wasshown to exhibit immunosuppressant activity in both in vitro and in vivomodels. (in et al., J. Exp. Med, 177: 637, 1993). The therapeuticutility of this compound, however, is limited by its potent toxicity.Recently, a class of compounds has been reported that may be anattractive alternative to the above-mentioned drugs (U.S. Pat. Nos.5,670,504; 5,631,282; 5,696,156; 5,679,705; and 5,696,156). Whileaddressing some of the activity/toxicity problems of previous drugs,these compounds tend to be of large molecular weight and are generallyproduced by synthetic manipulation of a natural product, isolation ofwhich is cumbersome and labor intensive.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmiain clinical practice and is likely to increase in prevalence with theaging of the population. Conservative estimates indicate that AFaffects >2 million Americans, represents over 5% of all admissions forcardiovascular diseases and leads to a 3- to 5-fold increase in the riskof stroke (Kannel et al, Am. J. Cardiol., 82:2N-9 N, 1998). While AF israrely fatal, it can impair cardiac function and lead to complicationssuch as the development of congestive heart failure, thromboembolism, orventricular fibrillation.

Reentrant excitation (reentry) has been shown to be a prominentmechanism underlying supraventricular arrhythmias in man (Nattel, S.,Nature, 415:219-226, 2002). Reentrant excitation requires a criticalbalance between slow conduction velocity and sufficiently briefrefractory periods to allow for the initiation and maintenance ofmultiple reentry circuits to coexist simultaneously and sustain AF.Increasing myocardial refractoriness by prolonging action potentialduration (APD) prevents and/or terminates reentrant arrhythmias. Actionpotential duration is determined by the contributions of therepolarizing potassium currents I_(Kr), I_(Ks), and I_(Kur), and thetransient outward current, I_(to). Blockers of any one of these currentswould therefore be expected to increase the APD and produceantiarrhythmic effects.

Currently available antiarrhythmic agents have been developed for thetreatment of ventricular and atrial/supraventricular arrhythmias.Malignant ventricular arrhythmias are immediately life-threatening andrequire emergency care. Drug therapy for ventricular arrhythmia includesClass Ia (eg. procainamide, quinidine), Class Ic (eg. flecainide,propafenone), and Class III (amiodarone) agents, which pose significantrisks of proarrhythmia. These Class I and III drugs have been shown toconvert AF to sinus rhythm and to prevent recurrence of AF (Mounsey, JP, DiMarco, J P, Circulation, 102:2665-2670), but pose an unacceptablerisk of potentially lethal ventricular proarrhythmia and thus mayincrease mortality (Pratt, C M, Moye, L A, Am J. Cardiol., 65:20B-29B,1990; Waldo et al, Lancet, 348:7-12, 1996; Torp-Pedersen et al, ExpertOpin. Invest. Drugs, 9:2695-2704, 2000). These observations demonstratea clear unmet medical need to develop safer and more efficacious drugsfor the treatment of atrial arrhythmias.

Class III antiarrhythmic agents cause a selective prolongation of theAPD without significant depression of cardiac conduction or contractilefunction. The only selective Class III drug approved for clinical use inatrial fibrillation is dofetilide, which mediates its anti-arrhythmiceffects by blocking I_(Kr), the rapidly activating component of I_(K)found in both atrium and ventricle in humans (Mounsey, J P, DiMarco, JP, Circulation, 102:2665-2670). Since I_(Kr) blockers increase APD andrefractoriness both in atria and ventricle without affecting conductionper se, theoretically they represent potentially useful agents for thetreatment of arrhythmias like AF (Torp-Pedersen, et al, Expert Opin.Invest. Drugs, 9:2695-2704, 2000). However, these agents have the majorliability of an enhanced risk of proarrhythmia at slow heart rates. Forexample, torsades de points has been observed when these compounds areutilized (Roden, D. M. “Current Status of Class III Antiarrhythmic DrugTherapy”, Am J. Cardiol., 72:44B49B, 1993). This exaggerated effect atslow heart rates has been termed “reverse frequency-dependence”, and isin contrast to frequency-independent or forward frequency-dependentactions (Hondeghem, L. M. “Development of Class III AntiarrhythmicAgents”. J. Cardiovasc. Cardiol., 20 (Suppl. 2):S17-S22). Amiodarone hasbeen shown to possess interesting Class III properties (Singh B. N.,Vaughan Williams E. M. “A Third Class Of Anti-Arrhythmic Action: EffectsOn Atrial And Ventricular Intracellular Potentials And OtherPharmacological Actions On Cardiac Muscle, of MJ 1999 and AH 3747” Br.J. Pharmacol., 39:675-689, 1970; Singh B. N., Vaughan Williams E. M,“The Effect Of Amiodarone, A New Anti-Anginal Drug, On Cardiac Muscle”,Br. J. Pharmacol., 39:657-667, 1970), although it is not a selectiveClass III agent because it effects multiple ion channels; additionally,its use is severely limited due to its side effect profile (Nademanee,K. “The Amiodarone Odyssey”. J. Am. Coll. Cardiol., 20:1063-1065, 1992;Fuster et al, Circulation, 104:2118-2150, 2001; Bril, A. Curr. Opin.Pharmacol. 2:154-159, 2002). Thus, currently available agents such asamiodarone and Class III drugs confer a significant risk of adverseeffects including the development of potentially lethal ventricularproarrhythmia.

The ultrarapid delayed rectifier K⁺ current, I_(Kur), has been observedspecifically in human atrium and not in ventricle. The molecularcorrelate of I_(Kur) in the human atrium is the potassium channeldesignated Kv1.5. Kv1.5 mRNA (Bertaso, Sharpe, Hendry, and James, BasicRes. Cardiol., 97:424-433, 2002) and protein (Mays, Foose, Philipson,and Tamkun, J. Clin. Invest., 96:282-292, 1995) have been detected inhuman atrial tissue. In intact human atrial myocytes, an ultra-rapidlyactivating delayed rectifier K⁺ current (I_(Kur)), also known as thesustained outward current, I_(sus) or I_(so), has been identified andthis current has properties and kinetics identical to those expressed bythe human K⁺ channel clone (hKv1.5, HK2) [Wang, Fermini and Nattel,Circ. Res., 73:1061-1076, 1993; Fedida et al., Circ. Res. 73:210-216,1993; Snyders, Tamkun and Bennett, J. Gen. Physiol., 101:513-543, 1993]and a similar clone from rat brain (Swanson et al., Neuron, 4:929-939,1990). Furthermore, because of its rapidity of activation and limitedslow inactivation, I_(Kur) is believed to contribute significantly torepolarization in human atrium. Consequently, a specific blocker ofI_(Kur), that is a compound which blocks Kv1.5, would overcome theshortcoming of other compounds by prolonging refractoriness throughretardation of the repolarization in the human atrium without causingthe delays in ventricular repolarization that underlie arrhythmogenicafter depolarizations and acquired long QT syndrome observed duringtreatment with current Class III drugs. Kv1.5 blockers exhibiting theseproperties have been described (Peukert et al, J. Med. Chem.,46:486-498, 2003; Knobloch et al, Naunyn-Schmedieberg's Arch. Pharmacol.366:482-287, 2002; Merck & Co., Inc. WO0224655, 2002).

The compounds described in this invention represent a novel structuralclass of Kv1.5 antagonist.

SUMMARY OF THE INVENTION

This invention relates to potassium channel inhibitors of generalstructural Formula I

The compounds of this invention are useful in the treatment andprevention of cardiac arrhythmias, and the like. Also within the scopeof this invention are pharmaceutical formulations comprising a compoundof Formula I and a pharmaceutical carrier.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present invention is a compound of formula I

or a pharmaceutically acceptable salt, crystal form, or hydrate,wherein:A is

a) an aryl ring, wherein any stable aryl ring atom is independentlyunsubstituted or substituted with

-   -   1) halogen,    -   2) NO₂,    -   3) CN,    -   4) CR⁴⁶═C(R⁴⁷R⁴⁸)₂,    -   5) C≡CR⁴⁶,    -   6) (CR^(i)R^(j))_(r)OR⁴⁶,    -   7) (CR^(i)R^(j))_(r)N(R⁴⁶R⁴⁷),    -   8) (CR^(i)R^(j))_(r)C(O)R⁴⁶,    -   9) (CR^(i)R^(j))_(r)C(O)OR⁴⁶,    -   10) (CR^(i)R^(j))_(r)R⁴⁶,    -   11) (CR^(i)R^(j))_(r)S(O)₀₋₂R⁶¹,    -   12) (CR^(i)R^(j))_(r)S(O)₀₋₂N(R⁴⁶R⁴⁷),    -   13) OS(O)₀₋₂R⁶¹,    -   14) N(R⁴⁶)C(O)R⁴⁷,    -   15) N(R⁴⁶)S(O)₀₋₂R⁶¹,    -   16) (CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹,    -   17) (CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹OR⁴⁷,    -   18) (CR^(i)R^(j))_(r)N(R⁴⁶)(CR^(k)R^(l))_(s)C(O)N(R⁴⁷R⁴⁸),    -   19) N(R⁴⁶)(CR^(i)R^(j))_(r)R⁶¹,    -   20) N(R⁴⁶)(CR^(i)R^(j))_(r)N(R⁴⁷R⁴⁸),    -   21) (CR^(i)R^(j))_(r)C(O)N(R⁴⁷R⁴⁸), or    -   22) oxo, or

b) a heteroaryl ring selected from the group consisting of

-   a 5-membered unsaturated monocyclic ring with 1, 2, 3 or 4    heteroatom ring atoms selected from the group consisting or N, O or    S,-   a 6-membered unsaturated monocyclic ring with 1, 2, 3 or 4    heteroatom ring atoms selected from the group consisting N, O and S,    and-   a 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3 or 4    heteroatom ring atoms selected from the group consisting or N, O or    S;-   wherein any stable S heteroaryl ring atom is unsubstituted or mono-    or di-substituted with oxo, and any stable C or N heteroaryl ring    atom is independently unsubstituted or substituted with    -   1) halogen,    -   2) NO₂,    -   3) CN,    -   4) CR⁴⁶═C(R⁴⁷R⁴⁸)₂,    -   5) C≡CR⁴⁶,    -   6) (CR^(i)R^(j))_(r)OR⁴⁶,    -   7) (CR^(i)R^(j))_(r)N(R⁴⁶R⁴⁷),    -   8) (CR^(i)R^(j))_(r)C(O)R⁴⁶,    -   9) (CR^(i)R^(j))_(r)C(O)OR⁴⁶,    -   10) (CR^(i)R^(j))_(r)R⁴⁶,    -   11) (CR^(i)R^(j))_(r)S(O)₀₋₂R⁶¹,    -   12) (CR^(i)R^(j))_(r)S(O)₀₋₂N(R⁴⁶R⁴⁷),    -   13) OS(O)₀₋₂R⁶¹,    -   14) N(R⁴⁶)C(O)R⁴⁷,    -   15) N(R⁴⁶)S(O)₀₋₂R⁶¹,    -   16) (CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹,    -   17) (CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹OR⁴⁷,    -   18) (CR^(i)R^(j))_(r)N(R⁴⁶)(CR^(k)R^(l))_(s)C(O)N(R⁴⁷R⁴⁸),    -   19) N(R⁴⁶)(CR^(i)R^(j))_(r)R⁶¹,    -   20) N(R⁴⁶)(CR^(i)R^(j))_(r)N(R⁴⁷R⁴⁸),    -   21) (CR^(i)R^(j))_(r)C(O)N(R⁴⁷R⁴⁸), or    -   22) oxo;

R¹ is selected from the group consisting of

-   -   1) hydrogen,    -   2) (CR^(a)R^(b))_(n)R⁴⁰    -   3) (CR^(a)R^(b))_(n)R⁴⁰,    -   4) (CR^(a)R^(b))_(n)N(R⁴⁰R⁴¹),    -   5) (CR^(a)R^(b))_(n)N(R⁴⁰)C(O)OR⁴¹,    -   6) (CR^(a)R^(b))_(n)N(R⁴⁰)(CR^(c)R^(d))₂N(R⁴¹)C(O)R⁴⁹,    -   7) C₃₋₈ cycloalkyl,    -   8) (CR^(a)R^(b))_(n)C(O)OR⁴⁰,    -   9) (CR^(a)R^(b))_(n)N(R⁴⁰)(CR^(c)R^(d))₁₋₃R⁴¹,    -   10) (CR^(a)R^(b))_(n)S(O)₀₋₂R⁶,    -   11) (CR^(a)R^(b))_(n)S(O)₀₋₂N(R⁴⁰R⁴¹),    -   12) (CR^(a)R^(b))_(n)N(R⁴⁰)R⁶OR⁴¹,    -   13) (CR^(a)R^(b))_(n)N(R⁴⁰)(CR^(c)R^(d))₀₋₆C(O)N(R⁴¹R⁴²);

R⁵ is —(CH₂)₂R²² or R⁸⁵;

R², R⁸, R⁹ and R¹⁰ are independently selected from:

-   -   1) hydrogen,    -   2) halogen,    -   3) NO₂,    -   4) CN,    -   5) CR⁴³═C(R⁴⁴R⁴⁵),    -   6) C≡CR⁴³,    -   7) (CR^(e)R^(f))_(p)OR⁴³,    -   8) (CR^(e)R^(f))_(p)N(R⁴³R⁴⁴),    -   9) (CR^(e)R^(f))_(p)C(O)R⁴³,    -   10) (CR^(e)R^(f))_(p)C(O)OR⁴³,    -   11) (CR^(e)R^(f))_(p)R⁴³,    -   12) (CR^(e)R^(f))_(p)S(O)₀₋₂R⁶⁰,    -   13) (CR^(e)R^(f))_(p)S(O)₀₋₂N(R⁴³R⁴⁴),    -   14) OS(O)₀₋₂R⁶⁰,    -   15) N(R⁴³)C(O)R⁴⁴,    -   16) N(R⁴³)S(O)₀₋₂R⁶⁰,    -   17) (CR^(e)R^(f))_(p)N(R⁴³)R⁶⁰,    -   18) (CR^(e)R^(f))_(p)N(R⁴³)R⁶⁰OR⁴⁴,    -   19) (CR^(e)R^(f))_(p)N(R⁴³)(CR^(g)R^(h))_(q)C(O)N(R⁴⁴R⁴⁵),    -   20) N(R⁴³)(CR^(e)R^(f))_(p)R⁶⁰,    -   21) N(R⁴³)(CR^(e)R^(f))_(p)N(R⁴⁴R⁴⁵), and    -   22) (CR^(e)R^(f))_(p)C(O)N(R⁴³R⁴⁴),    -   or R² and R⁸ are independently as defined above, and R⁹ and R¹⁰,        together with the atoms to which they are attached, form the        ring

where R^(m) is C₁₋₆alkyl;

R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j),R^(k), and R^(l) are independently selected from the group consistingof:

-   -   1) hydrogen,    -   2) C₁-C₆ alkyl,    -   3) halogen,    -   4) aryl,    -   5) R⁸⁰,    -   6) C₃-C₁₀ cycloalkyl, and    -   7) OR⁴,    -   said alkyl, aryl, and cycloalkyl being unsubstituted,        monosubstituted with R⁷, disubstituted with R⁷ and R¹⁵,        trisubstituted with R⁷, R¹⁵ and R¹⁶, or tetrasubstituted with        R⁷, R¹⁵, R¹⁶ and R¹⁷;

R⁴, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵¹, R⁵², R⁵³ andR⁵⁴ are independently selected from the group consisting of

-   -   1) hydrogen,    -   2) C₁-C₆ alkyl,    -   3) C₃-C₁₀ cycloalkyl,    -   4) aryl,    -   5) R⁸¹,    -   6) CF₃,    -   7) C₂-C₆ alkenyl, and    -   8) C₂-C₆ alkynyl,    -   said alkyl, aryl, and cycloalkyl is unsubstituted,        mono-substituted with R¹⁸, di-substituted with R¹⁸ and R¹⁹,        tri-substituted with R¹⁸, R¹⁹ and R²⁰, or tetra-substituted with        R¹⁸, R¹⁹, R²⁰ and R²¹;

R⁶, R⁶⁰, R⁶¹, and R⁶³ are independently selected from the groupconsisting of

-   -   1) C₁-C₆ alkyl,    -   2) aryl,    -   3) R⁸³, and    -   4) C₃-C₁₀ cycloalkyl;    -   said alkyl, aryl, and cycloalkyl is unsubstituted,        mono-substituted with R²⁶, di-substituted with R²⁶ and R²⁷,        tri-substituted with R²⁶, R²⁷ and R²⁸, or tetra-substituted with        R²⁶, R²⁷, R²⁸ and R²⁹;

R⁷, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²⁶, R²⁷, R²⁸, and R²⁹ areindependently selected from the group consisting of

-   -   1) C₁-C₆ alkyl,    -   2) halogen,    -   3) OR⁵¹,    -   4) CF₃,    -   5) aryl,    -   6) C₃-C₁₀ cycloalkyl,    -   7) R⁸⁴,    -   8) S(O)₀₋₂N(R⁵¹R⁵²),    -   9) C(O)OR⁵¹,    -   10) C(O)R⁵¹,    -   11) CN,    -   12) C(O)N(R⁵¹R⁵²),    -   13) N(R⁵¹)C(O)R⁵²,    -   14) S(O)₀₋₂R⁶³,    -   15) NO₂,    -   16) N(R⁵¹R⁵²), and    -   17) R⁸²;

R²² selected from the group consisting of

-   -   1) NHC(O)R⁸⁸, and    -   2) N(R⁵³R⁵⁴);

R⁸⁸ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl;

R⁸⁰, R⁸¹, R⁸², R⁸³, R⁸⁴ and R⁸⁵ are independently selected from a groupof unsubstituted or substituted heterocyclic rings consisting of a 3-6membered unsaturated or saturated monocyclic ring with 1, 2, or 3heteroatom ring atoms selected from the group consisting N, O and S, anda 9- or 10-membered unsaturated or saturated bicyclic ring with 1, 2, 3or 4 heteroatom ring atoms selected from the group consisting or N, O orS; and

n, p, q, r, and s are independently 0, 1, 2, 3, 4, 5 or 6.

In a class of compounds of the invention, or pharmaceutically acceptablesalts thereof,

A is an aryl ring selected from phenyl, unsubstituted or substituted asdefined above, or a heteroaryl ring, unsubstituted or substituted asdefined above, selected from the group consisting of pyridine,pyrimidine, pyrazine, pyridazine, indole, pyrrolopyridine,benzimidazole, benzoxazole, benzothiazole, and benzoxadiazole;

R², R⁸, R⁹ and R¹⁰ are independently selected from the group consistingof:

-   -   1) hydrogen,    -   2) halogen,    -   3) OR⁴³, and    -   4) (CR^(e)R^(f))_(p)R⁴³,    -   or R² and R⁸ are independently as defined above, and R⁹ and R¹⁰,        together with the atoms to which they are attached, form the        ring

where R^(m) is C₁₋₆alkyl;

R¹ is selected from the group consisting of

-   -   1) hydrogen,    -   2) (CR^(a)R^(b))₁₋₂R⁴⁰    -   3) (CR^(a)R^(b))₁₋₂OR⁴⁰,    -   4) (CR^(a)R^(b))₁₋₂N(R⁴⁰R⁴¹),    -   5) (CR^(a)R^(b))₁₋₂N(R⁴⁰)C(O)OR⁴¹,    -   6) (CR^(a)R^(b))₁₋₂N(R⁴⁰)(CR^(c)R^(d))₂N(R⁴¹)C(O)R⁴⁹,    -   7) (CR^(a)R^(b))₁₋₂C(O)OR⁴⁰,    -   8) (CR^(a)R^(b))₁₋₂N(R⁴⁰)(CR^(c)R^(d))₁₋₃R⁴¹, and    -   9) cyclopropyl.

In a subclass of the class of compounds, or pharmaceutically acceptablesalts thereof, R², R⁸, R⁹ and R¹⁰ are independently selected from thegroup consisting of hydrogen and (CR^(e)R^(f))_(p)OR⁴³.

In a group of the subclass of compounds, or pharmaceutically acceptablesalts thereof, R¹ is (CR^(a)R^(b))_(n)R⁴⁰ or C₃-C₁₀ cycloalkyl.

In a subgroup of the group of compounds, or pharmaceutically acceptablesalts thereof, A is an unsubstituted aryl ring.

In a family of the subgroup of compounds, or pharmaceutically acceptablesalts thereof,

R⁵ is selected from the group consisting of —(CH₂)₂NH₂,—(CH₂)₂NHC(O)CH₃, —(CH₂)₂N(CH₂CH₃)₂,

A preferred embodiment is a compound selected from the group consistingof

-   3-(2-Aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one,-   N-[2-(6-Methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]acetamide,-   6-Methoxy-2-methyl-4-phenyl-3-(2-piperidin-1-ylethyl)isoquinolin-1(2H)-one,-   6-Methoxy-2-methyl-3-[2-(2-oxopyrrolidin-1-yl)ethyl]-4-phenylisoquinolin-1(2R)-one,-   6-Methoxy-2-methyl-3-(2-morpholin-4-ylethyl)-4-phenylisoquinolin-1(2H)-one,-   3-[2-(Diethylamino)ethyl]-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one,-   N-[2-(6-Methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]-1-(4-methoxyphenyl)cyclopropanecarboxamide,-   1-Cyano-N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]cyclopropanecarboxamide,-   N-[2-(6-Methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]-1-(4-methoxyphenyl)acetamide,-   1-(2,4-Dichlorophenyl)-N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]cyclopropanecarboxamide,-   N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]-1-phenylcyclopropanecarboxamide,-   tert-Butyl    1-({[[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]amino}carbonyl)cyclopropyl    carbamate,-   1-Amino-N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]cyclopropanecarboxamide,-   4-Methoxy-N-[1-({[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]amino}carbonyl)cyclopropyl]benzamide,-   (±)-Benzyl    3-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)piperidine-1-carboxylate,-   (±)-6-Methoxy-2-methyl-4-phenyl-3-piperidin-3-ylisoquinolin-1(2H)-one,-   (±)-3-(1-Acetylpiperidin-3-yl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one,-   3-(1-acetylpiperidin-4-yl)-6-methoxy-2-methyl-phenylisoquinolin-1(2H)-one,-   6-methoxy-2-methyl-3-[1-(methylsulfonyl)piperidin-4-yl]-4-phenylisoquinolin-1(2H)-one,-   (±)-6-Methoxy-2-methyl-3-[1-(methylsulfonyl)piperidin-3-yl]-4-phenylisoquinolin-1(2H)-one,-   (±)-3-(1-Benzoylpiperidin-3-yl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one,-   3-(Pyrid-2-yl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one, and-   3-(Thiazol-2-yl)-6-methoxy-2-cyclopropyl-4-phenylisoquinolin-1(2H)-one,-   or a pharmaceutically acceptable salt thereof.

The above-listed compounds are active in one or more of the assays forKv1.5 described below.

Another embodiment of the invention is a method of treating orpreventing a condition in a mammal, the treatment or prevention of whichis effected or facilitated by K_(v)1.5 inhibition, which comprisesadministering an amount of a compound of Formula I that is effective atinhibiting K_(v)1.5.

A preferred embodiment is a method of treating or preventing cardiacarrhythmias, e.g. atrial fibrillation, atrial flutter, atrialarrhythmia, and supraventricular tachycardia, in a mammal, whichcomprises administering a therapeutically effective amount of a compoundof Formula I.

Another preferred embodiment is a method of preventing thromboembolicevents, such as stroke.

Another preferred embodiment is a method of preventing congestive heartfailure.

Another preferred embodiment is a method of treating or preventingimmunodepression or a disorder involving immunodepression, such as AIDS,cancer, senile dementia, trauma (including wound healing, surgery andshock) chronic bacterial infection, certain central nervous systemdisorders, and conditions including resistance by transplantation oforgans or tissue, graft-versus-host diseases brought about by medullaossium transplantation. Within this embodiment is a method for treatingor preventing immunodepression by administering a compound of theinvention with an immunosuppresant compound.

Another preferred embodiment is a method of treating or preventinggliomas including those of lower and higher malignancy, preferably thoseof higher malignancy.

Another preferred embodiment is a method for inducing in a patienthaving atrial fibrillation, a condition of normal sinus rhythm, in whichthe induced rhythm corresponds to the rhythm that would be considerednormal for an individual sharing with the patient similar size and agecharacteristics, which comprises treating the patient with a compound ofthe invention.

Another preferred embodiment is a method for treating tachycardia,(i.e., rapid heart rate e.g. 100 beats per minute) in a patient whichcomprises treating the patient with an antitachycardia device (e.g. adefibrillator or a pacemaker) in combination with a compound of claim 1.

The present invention also encompasses a pharmaceutical formulationcomprising a pharmaceutically acceptable carrier and the compound ofFormula I or a pharmaceutically acceptable crystal form or hydratethereof. A preferred embodiment is a pharmaceutical composition of thecompound of Formula I, comprising, in addition, a second agent.

The compounds of the present invention may have asymmetric centers orasymmetric axes, and this invention includes all of the optical isomersand mixtures thereof. Unless specifically mentioned otherwise, referenceto one isomer applies to both isomers.

In addition compounds with carbon-carbon double bonds may occur in Z-and E-forms with all isomeric forms of the compounds being included inthe present invention.

As used herein except where noted, “alkyl” is intended to include bothbranched- and straight-chain saturated aliphatic hydrocarbon groups,including all isomers, having the specified number of carbon atoms.Commonly used abbreviations for alkyl groups are used throughout thespecification, e.g. methyl may be represented by “Me” or CH₃, ethyl maybe represented by “Et” or CH₂CH₃, propyl may be represented by “Pr” orCH₂CH₂CH₃, butyl may be represented by “Bu” or CH₂CH₂CH₂CH₃, etc. “C₁-6alkyl” (or “C₁-C₆ alkyl”) for example, means linear or branched chainalkyl groups, including all isomers, having the specified number ofcarbon atoms. C₁₋₆ alkyl includes all of the hexyl alkyl and pentylalkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl,ethyl and methyl. “C₁₋₄ alkyl” means n-, iso-, sec- and t-butyl, n- andisopropyl, ethyl and methyl. The term “alkoxy” represents a linear orbranched alkyl group of indicated number of carbon atoms attachedthrough an oxygen bridge.

The term “alkenyl” includes both branched and straight chain unsaturatedhydrocarbon groups containing at least two carbon atoms joined by adouble bond. The alkene ethylene is represented, for example, by“CH₂CH₂” or alternatively, by “H₂C═CH₂”. “C₂₋₅ alkenyl” (or “C₂-C₅alkenyl”) for example, means linear or branched chain alkenyl groupshaving from 2 to 5 carbon atoms and includes all of the pentenyl isomersas well as 1-butenyl, 2-bentenyl, 3-butenyl, 1-propenyl, 2-propenyl, andethenyl (or ethylenyl). Similar terms such as “C₂₋₃ alkenyl” have ananalogous meaning.

The term “alkynyl” includes both branched and straight chain unsaturatedhydrocarbon groups containing at least two carbon atoms joined by atriple bond. The alkyne acetlyene is represented, for example, by “CHCH”or alternatively, by “HC≡CH”. “C₂₋₅ alkynyl” (or “C₂-C₅ alkynyl”) forexample, means linear or branched chain alkynyl groups having from 2 to5 carbon atoms and includes all of the pentynyl isomers as well as1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl, 2-propynyl, and ethynyl (oracetylenyl). Similar terms such as “C₂₋₃ alkynyl” have an analogousmeaning.

Unless otherwise noted, alkyl, alkenyl and alkynyl groups areunsubstituted or substituted with 1 to 3 substituents on each carbonatom, with halo, C₁-C₂₀ alkyl, CF₃, NH₂, N(C₁-C₆ alkyl)₂, NO₂, oxo, CN,N₃, —OH, —O(C₁-C₆ alkyl), C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, (C₀-C₆ alkyl) S(O)₀₋₂—, (C₀-C₆ alkyl)S(O)₀₋₂(C₀-C₆ alkyl)-,(C₀-C₆ alkyl)C(O)NH—, H₂N—C(NH)—, —O(C₁-C₆ alkyl)CF₃, (C₀-C₆alkyl)C(O)—, (C₀-C₆ alkyl)OC(O)—, (C₀-C₆ alkyl)O(C₁-C₆ alkyl)-, (C₀-C₆alkyl)C(O)₁₋₂(C₀-C₆ alkyl)-, (C₀-C₆ alkyl)OC(O)NH—, aryl, aralkyl,heterocycle, heterocyclylalkyl, halo-aryl, halo-aralkyl,halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl,cyano-heterocycle and cyano-heterocyclylalkyl.

The term “C₀” as employed in expressions such as “C₀₋₆ alkyl” means adirect covalent bond. Similarly, when an integer defining the presenceof a certain number of atoms in a group is equal to zero, it means thatthe atoms adjacent thereto are connected directly by a bond. Forexample, in the structure

wherein w is an integer equal to zero, 1 or 2, the structure is

when w is zero.

The term “C₃₋₈ cycloalkyl” (or “C₃-C₈ cycloalkyl”) means a cyclic ringof an alkane having three to eight total carbon atoms (i.e.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, orcyclooctyl). The terms “C₃₋₇ cycloalkyl”, “C₃₋₆ cycloalkyl”, “C₅₋₇cycloalkyl” and the like have analogous meanings.

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine andiodine (alternatively referred to as fluoro (F), chloro (Cl), bromo(Br), and iodo (I)).

The term “C₁₋₆ haloalkyl” (which may alternatively be referred to as“C₁-C₆ haloalkyl” or “halogenated C₁-C₆ alkyl”) means a C₁ to C₆ linearor branched alkyl group as defined above with one or more halogensubstituents. The term “C₁₋₄ haloalkyl” has an analogous meaning. Theterm “C₁₋₆ fluoroalkyl” has an analogous meaning except that the halogensubstituents are restricted to fluoro. Suitable fluoroalkyls include theseries (CH₂)₀₋₄CF₃ (i.e., trifluoromethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoro-n-propyl, etc.).

The term “carbocycle” (and variations thereof such as “carbocyclic” or“carbocyclyl”) as used herein, unless otherwise indicated, refers to (i)a C₃ to C₈ monocyclic, saturated or unsaturated ring or (ii) a C₇ to C₁₂bicyclic saturated or unsaturated ring system. Each ring in (ii) iseither independent of, or fused to, the other ring, and each ring issaturated or unsaturated. The carbocycle may be attached to the rest ofthe molecule at any carbon atom which results in a stable compound. Thefused bicyclic carbocycles are a subset of the carbocycles; i.e., theterm “fused bicyclic carbocycle” generally refers to a C₇ to C₁₀bicyclic ring system in which each ring is saturated or unsaturated andtwo adjacent carbon atoms are shared by each of the rings in the ringsystem. A fused bicyclic carbocycle in which one ring is saturated andthe other is saturated is a saturated bicyclic ring system. A fusedbicyclic carbocycle in which one ring is benzene and the other issaturated is an unsaturated bicyclic ring system. A fused bicycliccarbocycle in which one ring is benzene and the other is unsaturated isan unsaturated ring system. Saturated carbocyclic rings are alsoreferred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc.Unless otherwise noted, carbocycle is unsubstituted or substituted withC₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, aryl, halogen, NH₂ or OH. Asubset of the fused bicyclic unsaturated carbocycles are those bicycliccarbocycles in which one ring is a benzene ring and the other ring issaturated or unsaturated, with attachment via any carbon atom thatresults in a stable compound. Representative examples of this subsetinclude the following:

The term “aryl” refers to aromatic mono- and poly-carbocyclic ringsystems, wherein the individual carbocyclic rings in the polyringsystems are fused or attached to each other via a single bond. Suitablearyl groups include phenyl, naphthyl, and biphenylenyl.

The term “heterocycle” (and variations thereof such as “heterocyclic” or“heterocyclyl”) broadly refers to (i) a stable 4 to 8-membered,saturated or unsaturated monocyclic ring, or (ii) a stable 7- to12-membered bicyclic ring system, wherein each ring in (ii) isindependent of, or fused to, the other ring or rings and each ring issaturated or unsaturated, and the monocyclic ring or bicyclic ringsystem contains one or more heteroatoms (e.g., from 1 to 6 heteroatoms,or from 1 to 4 heteroatoms) selected from N, O and S and a balance ofcarbon atoms (the monocyclic ring typically contains at least one carbonatom and the ring systems typically contain at least two carbon atoms);and wherein any one or more of the nitrogen and sulfur heteroatoms isoptionally oxidized, and any one or more of the nitrogen heteroatoms isoptionally quaternized. The heterocyclic ring may be attached at anyheteroatom or carbon atom, provided that attachment results in thecreation of a stable structure. When the heterocyclic ring hassubstituents, it is understood that the substituents may be attached toany atom in the ring, whether a heteroatom or a carbon atom, providedthat a stable chemical structure results.

As used herein, the terms cycloalkyl, aryl, and heterocycle, unlessotherwise indicated, refer to unsubstituted and substituted moieties.Substituted cycloalkyl, e.g. substituted C3-C6 cycloalkyl, substitutedaryl, and substituted heterocycle are intended to include the cyclicgroup containing from 1 to 3 substituents in addition to the point ofattachment to the rest of the compound. Preferably, the substituents areselected from the group which includes, but is not limited to, halo,C₁-C₂₀ alkyl, CF₃, NH₂, N(C₁-C₆ alkyl)₂, NO₂, oxo, CN, N₃, —OH, —O(C₁-C₆alkyl), C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (C₀-C₆alkyl)S(O)₀₋₂—, (C₀-C₆ alkyl)S(O)₀₋₂(C₀-C₆ alkyl)-, (C₀-C₆alkyl)C(O)NH—, H₂N—C(NH)—, —O(C₁-C₆ alkyl)CF₃, (C₀-C₆ alkyl)C(O)—,(C₀-C₆ alkyl)OC(O)—, (C₀-C₆alkyl)O(C₁-C₆ alkyl)-, (C₀-C₆alkyl)C(O)₁₋₂(C₀-C₆ alkyl)-, (C₀-C₆ alkyl)OC(O)NH—, aryl, aryl-C(O)—,aryl-C(O)NH—, cyano, amino, —NHC(O)O—C₁-C₆ alkyl, aralkyl, heteroaryl,heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle,halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle andcyano-heterocyclylalkyl.

Saturated heterocyclics form a subset of the heterocycles; i.e., theterm “saturated heterocyclic” generally refers to a heterocycle asdefined above in which the entire ring system (whether mono- orpoly-cyclic) is saturated. The term “saturated heterocyclic ring” refersto a 4- to 8-membered saturated monocyclic ring or a stable 7- to12-membered bicyclic ring system which consists of carbon atoms and oneor more heteroatoms selected from N, O and S. Representative examplesinclude piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl,imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl(or tetrahydrofuranyl).

Heteroaromatics form another subset of the heterocycles; i.e., the term“heteroaromatic” (alternatively “heteroaryl”) generally refers to aheterocycle as defined above in which the entire ring system (whethermono- or poly-cyclic) is an aromatic ring system. The term“heteroaromatic ring” refers a 5- or 6-membered monocyclic aromatic ringor a 7- to 12-membered bicyclic which consists of carbon atoms and oneor more heteroatoms selected from N, O and S. Representative examples ofheteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl,pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl,thiazolyl, isothiazolyl, and thiadiazolyl.

Representative examples of bicyclic heterocycles include benzotriazolyl,indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl,quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl,quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1,4-dioxinyl

imidazo(2,1-b)(1,3)thiazole,

and benzo-1,3-dioxolyl

In certain contexts herein,

is alternatively referred to as phenyl having as a substituentmethylenedioxy attached to two adjacent carbon atoms.

Unless expressly stated to the contrary, an “unsaturated” ring is apartially or fully unsaturated ring. For example, an “unsaturatedmonocyclic C₆ carbocycle” refers to cyclohexene, cyclohexadiene, andbenzene.

Unless expressly stated to the contrary, all ranges cited herein areinclusive. For example, a heterocycle described as containing from “1 to4 heteroatoms” means the heterocycle can contain 1, 2, 3 or 4heteroatoms.

When any variable occurs more than one time in any constituent or in anyformula depicting and describing compounds of the invention, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Also, combinations of substituents and/or variablesare permissible only if such combinations result in stable compounds.

The term “substituted” (e.g., as in “aryl which is optionallysubstituted with one or more substituents . . . ”) includes mono- andpoly-substitution by a named substituent to the extent such single andmultiple substitution (including multiple substitution at the same site)is chemically allowed.

In compounds of the invention having pyridyl N-oxide moieties, thepyridyl-N-oxide portion is structurally depicted using conventionalrepresentations such as

which have equivalent meanings.

For variable definitions containing terms having repeated terms, e.g.,(CR^(i)R^(j))_(r), where r is the integer 2, R^(i) is a definedvariable, and R^(j) is a defined variable, the value of R^(i) may differin each instance in which it occurs, and the value of R^(j) may differin each instance in which it occurs. For example, if R^(i) and R^(j) areindependently selected from the group consisting of methyl, ethyl,propyl and butyl, then (CR^(i)R^(j))₂ can be

Pharmaceutically acceptable salts include both the metallic (inorganic)salts and organic salts; a list of which is given in Remington'sPharmaceutical Sciences, 17th Edition, pg. 1418 (1985). It is well knownto one skilled in the art that an appropriate salt form is chosen basedon physical and chemical stability, flowability, hydro-scopicity andsolubility. As will be understood by those skilled in the art,pharmaceutically acceptable salts include, but are not limited to saltsof inorganic acids such as hydrochloride, sulfate, phosphate,diphosphate, hydrobromide, and nitrate or salts of an organic acid suchas malate, maleate, fumarate, tartrate, succinate, citrate, acetate,lactate, methanesulfonate, p-toluenesulfonate or palmoate, salicylateand stearate. Similarly pharmaceutically acceptable cations include, butare not limited to sodium, potassium, calcium, aluminum, lithium andammonium (especially ammonium salts with secondary amines). Preferredsalts of this invention for the reasons cited above include potassium,sodium, calcium and ammonium salts. Also included within the scope ofthis invention are crystal forms, hydrates and solvates of the compoundsof Formula I.

Methods for preparing the compounds of this invention are illustrated inthe following schemes, in which variables R¹ and R⁹ are as definedabove, and R is C₁₋₆ alkyl, aryl, or C₁₋₆ alkylaryl. Other syntheticprotocols will be readily apparent to those skilled in the art.

The following examples illustrate the preparation of the compounds ofFormula I and as such are not to be considered as limiting the inventionset forth in the claims appended hereto.

Example 13-(2-Aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-onehydrochloride

Step A: 3-(Bromomethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one

The titled compound was prepared using a synthetic procedure previouslyreported in WO 02/24655.

Step B: 3-(Cyanomethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2-one

To a solution of3-(bromomethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (6.82g, 19.0 mmol) in 100 mL of isopropanol was added a solution of potassiumcyanide (2.48 g, 38.1 mmol) in 10 mL of water. The mixture was heated at80° C. After one hour, another portion of potassium cyanide solution(300 mg in 5 mL of water) was added, and the reaction stirred for anadditional hour. The solution was cooled to room temperature, andpartitioned between EtOAc and saturated NaHCO₃ solution. The aqueouslayer was extracted twice with EtOAc, and the combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo. The crude solid material was triturated with EtOAc/ether toprovide the titled product (5.01 g, 86% yield). HRMS (ES) exact masscalculated for C₁₉H₁₆N₂O₂ (M+H⁺): 305.1285. Found 305.1269.

Step C:3-(2-Aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-onehydrochloride

To a solution of3-(cyanomethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (2.00g, 6.57 mmol) in 150 mL of 15% ammonium hydroxide in methanol in a Parrflask was added Raney nickel (˜5 g of a 50% slurry in water). Themixture was shaken under 60 psi of hydrogen at room temperature for 2hours, then filtered through a pad of celite, along with a methanolrinse. The resulting solution was concentrated in vacuo, then azeotropedfrom toluene to remove remaining ammonia and water. The residue wa takenup in a solution of dichloromethane and methanol, filtered, andconcentrated in vacuo. The product was taken up in a minimal amount ofdichloromethane, treated with excess ethereal HCl, filtered, andtriturated with dichloromethane-ether solution to provide the titled HClsalt. ¹H-NMR (500 MHz, CDCl₃) δ 8.39 (d, J=8.8 Hz, 1H), 7.48 (m, 2H),7.43 (m, 1H), 7.25 (m, 2H), 7.00 (dd, J=8.8, 2.5 Hz, 1H), 6.25 (d, J=2.5Hz, 1H), 3.71 (s, 3H), 3.66 (s, 3H), 2.85 (br t, J=7 Hz, 2H), 2.68 (brt, J=7 Hz, 2H), 1.65 (br s, 2H) ppm. HRMS (ES) exact mass calculated forC₁₉H₂₁N₂O₂ (M+H⁺): 309.1589. Found 309.1598.

Example 2N-[2-(6-Methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]acetamide

To a solution of3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-onehydrochloride (75 mg, 0.22 mmol) in 2 mL of dichloromethane was addedtriethylamine (0.076 mL, 0.54 mmol), followed by acetyl chloride (0.017mL, 0.24 mmol). After 45 minutes, the mixture was partitioned betweenEtOAc and 10% citric acid solution, and the organic layer was washedwith saturated NaHCO₃ solution and brine, dried over Na₂SO₄, filtered,and concentrated in vacuo. The crude residue was purified by preparativereversed phase HPLC to provide the titled product as a colorless oil.Proton NMR for the product was consistent with the titled compound. HRMS(ES) exact mass calculated for C₂₁H₂₂N₂O₃ (M+H⁺): 351.1703. Found351.1681.

Example 36-Methoxy-2-methyl-4-phenyl-3-(2-piperidin-1-ylethyl)isoquinolin-1(2H)-onehydrochloride

To a solution of3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-onehydrochloride (100 mg, 0.290 mmol) in 15 mL of 2-methyl-2-propanol in apressure tube was added triethylamine (0.142 mL, 1.02 mmol), followed by1,5-dibromopentane (0.047 mL, 0.348 mmol). The mixture was heated at150° C. overnight. Another portion of 1,5-dibromopentane was added(0.023 mL), and the heating continued for another 24 hours. Aftercooling to room temperature, the mixture was concentrated in vacuo. Thecrude residue was purified by preparative reversed phase HPLC. The purefractions were concentrated in vacuo, taken up in EtOAc and washed withsaturated NaHCO₃ solution and brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The product was taken up in dichloromethane,treated with excess ethereal HCl, and concentrated in vacuo to providethe HCl salt. Proton NMR for the product was consistent with the titledcompound. ESI+MS: 377.19 [M+H]⁺.

Example 46-Methoxy-2-methyl-3-[2-(2-oxopyrrolidin-1-yl)ethyl]-4-phenylisoquinolin-1(2H)-one

To a solution of3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-onehydrochloride (125 mg, 0.362 mmol) in 15 mL of dichloromethane was addedtriethylamine (0.202 mL, 1.45 mmol), followed by 4-chlorobutanoylchloride (0.045 mL, 0.40 mmol). After 45 minutes, the mixture wasconcentrated in vacuo. Tetrahydrofuran was added (15 mL), and thesolution was cooled to 0° C. Sodium hydride was added (58 mg, 60%dispersion in mineral oil, 1.45 mmol). The reaction mixture was stirredat 0° C. for 30 minutes, at room temperature for 16 hours, then at 50°C. for 2 hours. The solution was partitioned between EtOAc and saturatedNaHCO₃ solution, and the organic layer was washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude residue waspurified by preparative reversed phase HPLC to provide the titledproduct. Proton NMR for the product was consistent with the titledcompound. ESI+MS: 377.27 [M+H]⁺.

Example 56-Methoxy-2-methyl-3-(2-morpholin-4-ylethyl)-4-phenylisoquinolin-1(2H)-onehydrochloride

Following the procedure described in Example 3, replacing1,5-dibromopentane with di-(2-bromoethyl)ether, the titled compound wasobtained. Proton NMR for the product was consistent with the titledcompound. ¹H-NMR (500 MHz, d₆-DMSO) δ 10.69 (br s, 1H), 8.23 (d, J=9.0Hz, 1H), 7.57 (m, 2H), 7.52 (m, 1H), 7.35 (br d, J=7 Hz, 2H), 7.13 (dd,J=9.0, 2.4 Hz, 1H), 6.16 (d, J=2.4 Hz, 1H), 3.90 (m, 2H), 3.67 (s, 3H),3.65 (m, 2H), 3.63 (s, 3H), 3.23 (m, 4H), 2.98 (m, 2H), 2.88 (m, 2H)ppm. HRMS (ES) exact mass calculated for C₂₃H₂₇N₂O₃ (M+H⁺): 379.2016.Found 379.2018.

Example 63-[2-(Diethylamino)ethyl]-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-onetrifluoroacetate

To a solution of3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-onehydrochloride (100 mg, 0.290 mmol) in 3 mL of 1,2-dichloroethane wasadded acetaldehyde (0.017 mL, 0.29 mmol), sodium triacetoxyborohydride(92 mg, 0.43 mmol), and 100 mg of powdered 4 Å molecular sieves. Aftertwo hours, additional portions of acetaldehyde (0.017 mL, 0.29 mmol) andsodium triacetoxyborohydride (92 mg, 0.43 mmol) were added, and thereaction was stirred for 3 days. The mixture was partitioned betweenEtOAc and 10% citric acid solution, and the organic layer was washedwith saturated NaHCO₃ solution and brine, dried over Na₂SO₄, filtered,and concentrated in vacuo. The crude residue was purified by preparativereversed phase HPLC to provide the titled product. Proton NMR for theproduct was consistent with the titled compound. ESI+MS: 365.21 [M+H]⁺.

Example 7N-[2-(6-Methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]-1-(4-methoxyphenyl)cyclopropanecarboxamide

To a solution of3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-onehydrochloride (70 mg, 0.20 mmol) in 3 mL of dimethylformamide was added1-(4-methoxyphenyl)cyclopropanecarboxylic acid (0.39 mg, 0.20 mmol),triethylamine (0.085 mL, 0.61 mmol), 1-hydroxybenzotriazole hydrate (37mg, 0.24 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (47 mg, 0.24 mmol). After three hours, the mixture waspartitioned between EtOAc and water, and the organic layer was washedwith saturated NaHCO₃ solution and brine, dried over Na₂SO₄, filtered,and concentrated in vacuo. The crude residue was triturated withether-hexane solution to provide the titled product. HRMS (ES) exactmass calculated for C₃₀H₃₀N₂O₄ (M+H⁺): 483.2258. Found 483.2279.

Example 81-Cyano-N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]cyclopropanecarboxamide

Following the procedure described in Example 7, replacing1-(4-methoxyphenyl)cyclopropanecarboxylic acid with1-cyano-1-cyclopropanecarboxylic acid, the titled compound was obtained.Proton NMR for the product was consistent with the titled compound. HRMS(ES) exact mass calculated for C₂₄H₂₃N₃O₃ (M+H⁺): 402.1812. Found402.1803.

Example 9N-[2-(6-Methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]-1-(4-methoxyphenyl)acetamide

Following the procedure described in Example 7, replacing1-(4-methoxyphenyl)cyclopropanecarboxylic acid with1-(4-methoxyphenyl)acetic acid, the titled compound was obtained afterpurification by preparative reversed phase HPLC. Proton NMR for theproduct was consistent with the titled compound. HRMS (ES) exact masscalculated for C₂₈H₂₈N₂O₄ (M+H⁺): 457.2122. Found 457.2112.

Example 101-(2,4-Dichlorophenyl)-N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]cyclopropanecarboxamide

Following the procedure described in Example 7, replacing1-(4-methoxyphenyl)cyclopropanecarboxylic acid with1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid, the titled compoundwas obtained after purification by preparative reversed phase HPLC.Proton NMR for the product was consistent with the titled compound. HRMS(ES) exact mass calculated for C₂₉H₂₆Cl₂N₂O₃ (M+H⁺): 521.1393. Found521.1379.

Example 11N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]-1-phenylcyclopropanecarboxamide

Following the procedure described in Example 7, replacing1-(4-methoxyphenyl)cyclopropanecarboxylic acid with1-phenylcyclopropane-1-carboxylic acid, the titled compound was obtainedafter purification by preparative reversed phase HPLC. ¹H-NMR (500 MHz,CDCl₃) δ 8.39 (d, J=8.8 Hz, 1H), 7.38-7.45 (m, 3m), 7.25-7.30 (m, 5H),7.11 (m, 2H), 7.00 (dd, J=8.8, 2.5 Hz, 1H), 6.17 (d, J=2.5 Hz, 1H), 5.34(m, 1H), 3.80 (s, 3H), 3.65 (s, 3H), 3.21 (m, 2H), 2.68 (m, 2H), 1.57(m, 2H), 1.02 (dd, J=6.8, 3.7 Hz, 2H) ppm. HRMS (ES) exact masscalculated for C₂₉H₂₈N₂O₃ (M+H⁺): 453.2173. Found 453.2158.

Example 12 tert-Butyl1-({[[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]amino}carbonyl)cyclopropylcarbamate

Following the procedure described in Example 7, replacing1-(4-methoxyphenyl)cyclopropanecarboxylic acid withN-(tert-butoxycarbonyl)-1-amino-1-cyclopropanecarboxylic acid, thetitled compound was obtained. Proton NMR for the product was consistentwith the titled compound. HRMS (ES) exact mass calculated for C₂₈H₃₃N₃O₅(M+H⁺): 492.2493. Found 492.2481.

Example 131-Amino-N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]cyclopropanecarboxamidehydrochloride

Through a solution of tert-butyl1-({[[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]amino}carbonyl)cyclopropylcarbamate (ca. 100 mg) in 10 mL of EtOAc at 0° C. was bubbled anhydrousHCl gas for 3 minutes. The solution was stirred for one hour, thenconcentrated in vacuo to provide the titled salt. Proton NMR for theproduct was consistent with the titled compound. HRMS (MS) exact masscalculated for C₂₃H₂₅N₃O₃ (M+H⁺): 392.1969. Found 392.1960.

Example 144-Methoxy-N-[1-({[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]amino}carbonyl)cyclopropyl]benzamide

To a solution of1-amino-N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]cyclopropanecarboxamidehydrochloride (30 mg, 0.117 mmol) in 3 mL of dimethylformamide was addedtriethylamine (0.049 mL, 0.35 mmol), followed by 4-(methoxy)benzoylchloride (24 mg, 0.14 mmol). After 3 days, the mixture was concentratedin vacuo. Purification by preparative reversed phase HPLC provided thetitled compound. ESI+MS: 526.0 [M+H]⁺.

Example 15 (±)-Benzyl3-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)piperidine-1-carboxylate

Step A: (±)-1-[(Benzyloxy)carbonyl]piperidine-3-carboxylic acid

To an ice cooled solution of nipecotic acid (10.0 g, 77.5 mmol), sodiumhydroxide (3.4 g, 85 mmol), and tetrahydrofuran (50 mL) in water (100mL) was added by simultaneous dropwise addition benzylchloroformate(13.3 mL, 93 mmol) in tetrahydrofuran (50 mL) and sodium hydroxide (3.4g, 85 mmol) in water (50 mL). Warmed slowly to room temperature. After24 hours tetrahydrofuran was removed in vacuo and the resulting aqueousmixture acidified with 3 N hydrochloric acid and extracted withdichloromethane (3×). The combined organic portions were dried withanhydrous magnesium sulfate. Filtration followed by evaporation of thefiltrate in vacuo gave the titled compound. ¹HNMR (CHCl₃, 300 MHz) □7.45-7.20 (m, 5H); 5.14 (m, 2H); 4.21 (br s, 1H); 3.96 (m, 1H), 3.15 (brs, 1H); 2.93 (m, 1H); 2.51 (m, 1H); 2.09 (m, 1H); 1.80-1.60 (m, 2H);1.50 (m, 1H) ppm.

Step B: (±)-Benzyl-3-(chlorocarbonyl)piperidine-1-carboxylate

To an ice cooled methylene chloride solution of1-[(Benzyloxy)carbonyl]piperidine-3-carboxylic acid (512 mg, 1.95 mmol)under nitrogen was added oxalyl chloride (0.185 mL, 1.95 mmol) and a fewdrops N,N-dimethylformamide. The reaction flask was warmed slowly toroom temperature and after 2 hours the solvent was removed in vacuo.Toluene was added and removed in vacuo (2×) to give the title compound.

Step C: 4-Methoxy-N-methyl-2-(phenylmethyl)benzamide

The titled compound was prepared using a synthetic procedure previouslyreported in WO 02/24655.

Step D: (±)-Benzyl3-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)piperidine-1-carboxylate

To an isopropanol-dry ice cooled solution of4-methoxy-N-methyl-2-(phenylmethyl)benzamide (500 mg, 1.96 mmol) intetrahydrofuran (90 mL) was added dropwise a 1.3 M solution ofsec-butyllithium (3.09 mL, 4.02 mmol). After 15 min. a solution of(±)-benzyl-3-(chlorocarbonyl)piperidine-1-carboxylate (550 mg, 1.96mmol) in tetrahydrofuran (10 mL) was added. After 0.5 hours the contentsof the reaction flask were first warmed to room temperature and then thesolvent was removed in vacuo. The resulting mixture was treated with 1 Mhydrochloric acid and extracted (3×) with ethyl acetate. The combinedorganic extracts were dried with anhydrous sodium sulfate, filtered andevaporated in vacuo. Trifluoroacetic acid (1 mL) was added and theresulting solution stirred 10 min. The reaction was quenched with waterand made basic with saturated sodium bicarbonate. Extracted with ethylacetate (3×), dried combined organic extracts with anhydrous sodiumsulfate and removed solvent in vacuo to give a white foam. Flash columnchromatography (50% EtOAc/hexane) afforded the title compound as a whitefoam. Proton NMR for the product was consistent with the titledcompound. ESI+MS: 483.3 [M+H]⁺.

Example 16(±)-6-Methoxy-2-methyl-4-phenyl-3-piperidin-3-ylisoquinolin-1(2H)-one

To an ethanol (15 mL) solution of (±)-benzyl3-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)piperidine-1-carboxylate(201 mg, 0.417 mmol) in a Parr hydrogenation jar was added 10% palladiumon carbon catalyst (50 mg). The contents of the jar were hydrogenated at60 psi for four hours. Filtration through celite followed by evaporationof the filtrate in vacuo gave the titled product as a white foam. ProtonNMR for the product was consistent with the titled compound. ESI+MS:349.2 [M+H]⁺.

Example 17(±)-3-(1-Acetylpiperidin-3-yl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one

To a dichloromethane (0.100 mL) solution of(±)-6-methoxy-2-methyl-4-phenyl-3-piperidin-3-ylisoquinolin-1(2H)-one(30 mg, 0.086 mmol) and N,N-diisopropylethylamine (0.017 mL, 0.095 mmol)was added acetyl chloride (0.007 mL, 0.095 mmol). After 24 hourssaturated sodium bicarbonate and additional dichloromethane were added.The layers were separated and the organic phase dried with anhydrousmagnesium sulfate. Evaporation of the solvent in vacuo followed bytrituration with ether-EtOAc gave a white solid which was isolated byvacuum filtration to give the titled product. ESI+MS: 391.3 [M+H]⁺.

Example 18(±)-6-Methoxy-2-methyl-3-[1-(methylsulfonyl)piperidin-3-yl]-4-phenylisoquinolin-1(2H)-one

To a methylene chloride (0.100 mL) solution of(±)-6-methoxy-2-methyl-4-phenyl-3-piperidin-3-ylisoquinolin-1(2H)-one(30 mg, 0.086 mmol) and N,N-diisopropylethylamine (0.017 mL, 0.095 mmol)was added methanesulfonyl chloride (0.007 mL, 0.095 mmol). After 24hours saturated sodium bicarbonate and additional methylene chloridewere added. The layers were separated and the organic phase dried withanhydrous magnesium sulfate. Evaporation of the solvent in vacuofollowed by trituration with ether-EtOAc gave a white solid which wasisolated by vacuum filtration to give the titled product. ESI+MS: 427.1[M+H]⁺.

Example 19(±)-3-(1-Benzoylpiperidin-3-yl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one

To a dichloromethane (0.100 mL) solution of(±)-6-methoxy-2-methyl-4-phenyl-3-piperidin-3-ylisoquinolin-1(2H)-one(30 mg, 0.086 mmol) and N,N-diisopropylethylamine (0.017 mL, 0.095 mmol)was added benzoyl chloride (0.011 mL, 0.095 mmol). After 24 hourssaturated sodium bicarbonate and additional dichloromethane were added.The layers were separated and the organic phase dried with anhydrousmagnesium sulfate. Evaporation of the solvent in vacuo followed bytrituration with ether-EtOAc gave a white solid which was isolated byvacuum filtration to give the titled product. ESI+MS: 453.3 [M+H]⁺.

Example 20

3-(1-Acetylpiperidin-4-yl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one

Step A

To an isopropanol/dry ice cooled solution of4-Methoxy-N-methyl-2-(phenylmethyl)benzamide (250 mg, 0.980 mmol) in THF(50 mL) under argon was added sec-butyllithium solution (1.3M, 1.55 mL,2.00 mmol) dropwise. After 10 min. a THF (10 mL) solution ofbenzyl-4-(chlorocarbonyl)piperidine-1-carboxylate (275 mg, 980 mmol) wasquickly added to the reaction solution. After 10 min. the reaction wasquenched with water then warmed to room temperature. Saturated sodiumbicarbonate was added and the resulting mixture extracted with ethylacetate (3×) and dried with anhydrous magnesium sulfate. Filtrationfollowed by evaporation of solvent in vacuo gave the crude product whichwas subjected to flash column chromatography (hexane:ethyl acetate50:50) to affordbenzyl-4-(3-hydroxy-6-methoxy-2-methyl-1-oxo-4-phenyl-1,2,3,4-tetra-hydroisoquinolin-3-yl)piperidine-1-carboxylateas a white foam (242 mg, 0.484 mmol, 49%). MS [M+H]⁺ 501.2

Step B

To trifluoroacetic acid (1 mL) at room temperature was addedbenzyl-4-(3-hydroxy-6-methoxy-2-methyl-1-oxo-4-phenyl-1,2,3,4-tetra-hydroisoquinolin-3-yl)piperidine-1-carboxylate(215 mg, 0.443 mmol) with stirring. After 10 min. the reaction mixturewas made basic with 2N sodium hydroxide, extracted with methylenechloride (3×) and dried with anhydrous sodium sulfate. Filtrationfollowed by evaporation of solvent in vacuo gave a solid which wastriturated with hexane-ethyl acetate to affordbenzyl-4-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)piperidine-1-carboxylateas a solid (141 mg, 0.292 mmol, 66%). MS [M+H]⁺ 483.2

Step C

To a Parr bottle containing an ethanol (5 mL) solution ofbenzyl-4-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)piperidine-1-carboxylate(120 mg, 0.249 mmol) was added 10% palladium on carbon catalyst (30 mg).The contents of the Parr bottle were hydrogenated at 60 psi for 3 h.Filtration of the reaction mixture through celite followed byevaporation of the solvent in vacuo gave, after trituration with ether,6-Methoxy-2-methyl-4-phenyl-3-piperidin-4-ylisoquinolin-1(2H)-one as asolid (60 mg, 0.172 mmol, 69%). MS [M+H]⁺ 349.1

Step D

To a stirred methylene chloride (0.300 mL) solution of6-Methoxy-2-methyl-4-phenyl-3-piperidin-4-ylisoquinolin-1(2H)-one (20mg, 0.057 mmol) and N,N-diisopropylethylamine (0.011 mL, 0.063 mmol)under argon was added acetyl chloride (0.005 mL, 0.063 mmol). After 24 hsaturated sodium bicarbonate was added and the organic layer separatedand dried with anhydrous magnesium sulfate. Filtration followed byremoval of the solvent in vacuo gave a solid which after triturationwith ether-ethyl acetate afforded the titled compound as a solid.

MS [M+H]⁺ 391.1

Example 21

6-Methoxy-2-methyl-3-[1-(methylsulfonyl)piperidin-4-yl]-4-phenyl-isoquinolin-1(2H)-one

To a stirred methylene chloride (0.300 mL) solution of6-Methoxy-2-methyl-4-phenyl-3-piperidin-4-ylisoquinolin-1(2H)-one (20mg, 0.057 mmol) and N,N-diisopropylethylamine (0.011 mL, 0.063 mmol)under argon was added methanesulfonyl chloride (0.005 mL, 0.063 mmol).After 24 h saturated sodium bicarbonate was added and the organic layerseparated and dried with anhydrous magnesium sulfate. Filtrationfollowed by removal of the solvent in vacuo gave a solid which aftertrituration with ether-ethyl acetate afforded the titled compound as asolid.

MS [M+H]⁺ 427.1

Using the methodologies described below, representative compounds of theinvention were evaluated and found to exhibit activity in the Kv1.5assays, thereby demonstrating and confirming the utility of thecompounds of this invention as Kv1.5 inhibitors and antiarrhythmics.Compounds of this type may exhibit forward rate-dependence, blocking theoutward K⁺ currents to a greater extent or preferentially at fasterrates of depolarization or heart rates. Such a compound could beidentified in electrophysiological studies as described below. Forexample, during a train of depolarizations delivered at frequencies of 1Hz and 3 Hz, the block is “rate-dependent” if the amount of blockobserved during a 10 second train at 3 Hz is greater than that at 1 Hz.A Kv1.5 blocker may also display use-dependence, during which the blockof the outward K⁺ currents increases with use, or during repetitivedepolarization of a cardiac cell. Use dependence of block occurs to agreater extent with each successive depolarization in a train orsequence of pulses or depolarizations at a given rate or frequency. Forexample, during a train of 10 depolarizations at a frequency of 1 Hz,the block is “use-dependent” if the amount of block is greater for the10^(th) pulse than for the 1^(st) pulse of the train. A Kv1.5 blockermay exhibit both use-dependence and rate-dependence.

A Kv1.5 blocker may also be identified through electrophysiologicalstudies of native I_(Kur) using cardiac myocytes or other tissue fromvarious species including, but not limited to, human, rat, mouse, dog,monkey, ferret, rabbit, guinea pig, or goat. In native tissues Kv1.5 mayexist as a homo-oligomer, or as a hetero-oligomer with other Kv familymembers, or may exist in a complex with a β-subunit. Compounds of thisinvention may block Kv1.5 homo- or hetero-oligomers or Kv1.5 incomplexes with β-subunits.

Kv1.5 Assays

The high throughput Kv1.5 planar patch clamp assay is a systematicprimary screen. It confirms activity and provides a functional measureof the potency of agents that specifically affect Kv1.5 potassiumchannels. Kiss et al. (Assay and Drug Dev. Tech., 1(1-2):127-135, 2003)and Schroeder et al. (J. of Biomol. Screen., 8(1); 50-64, 2003) describethe use of this instrument for Kv1.5 as well as other voltage gated ionchannels.

Chinese hamster ovary cells (CHO) stably expressing the human Kv1.5potassium channel alpha subunit, cloned from human heart, are grown to90-100% confluence in Ham's F12 medium supplemented with 10% FBS, 100μg/ml penicillin, 100 μg/ml streptomycin, 1000 μg/ml G-418 sulfate.Cells are subcultured by treatment with Versene, then suspended inphosphate-buffered saline PBS) and centrifuged The cell pellet isresuspended in PBS and the resulting suspension placed in the cellreservoir of the IonWork™ HT instrument.

Electrophysiological recordings are performed with intracellularsolution containing (mM): K-gluconate 100, KCl 40, MgCl₂ 3.2, EGTA 3,N-2-hydroxylethylpiperazine-N¹-2-ethanesulphonic acid (HEPES) 5,adjusted to pH 7.3. Amphotericin (Sigma) is prepared as 30 mg/ml stocksolution and diluted to a final working concentration of 0.1 mg/ml ininternal buffer solution. The external solution is Dulbecco's PBS(Invitrogen) and contains (mM): CaCl₂ 0.90, KCl 2.67, KPO₄ 1.47, MgCl₂0.50, NaCl 138, NaPO₄ 8.10 and has a pH of 7.4. All compounds areprepared as 10 mM stock solutions in DMSO. Compounds are diluted intoexternal buffer, then transferred from the drug plate to the Patchplateduring the experiment (final DMSO concentration <0.66% vol.).

Kv1.5 ionic currents are recorded at room temperature. Membrane currentsare amplified (RMS ˜10 pA) and sampled at 10 kHz. Leak subtraction wasperformed in all experiments by applying a 160 ms hyperpolarizing (10mV) pre-pulses 200 ms before the test pulses to measure leakconductance. The patch clamp stimulus protocol is as follows:

-   -   1. Patchplate wells are loaded with 3.5 μL of external buffer.    -   2. Planar micropipette hole resistances (Rp) is determined by        applying a 10 mV, 160 ms potential difference across each hole        (Hole test).    -   3. Cells are pipetted into the Patchplate and form high        resistance seals with the 1-2 μm holes at the bottom of each        Patchplate well. A seal test scan is performed to determine how        many of the Patchplate wells have cells that have formed seals.    -   4. In order to gain electrical access to the cells,        intracellular solution containing amphotericin is circulated for        4 minutes on the bottom side of the Patchplate.    -   5. Pre-compound addition test pulse is applied to each well on        the Patchplate. Protocol: Cells are voltage clamped at a        membrane holding potential of −80 mV for 15 seconds. This is        followed by application of a 5 Hz stimulus train (27×150 ms        depolarizations to +40 mV). The membrane potential steps to +40        mV evoke outward (positive) ionic currents.    -   6. Compound is added to each well of the Patchplate. Compounds        are allowed to incubate for 5 minutes.    -   7. Post-compound addition test pulse protocol is applied.        Protocol: Cells are voltage clamped at a membrane holding        potential of −80 mV for 15 seconds. This is followed by        application of a 5 Hz stimulus train (27×150 ms depolarizations        to +40 mV).

Data analysis is conducted off-line. Paired comparisons between pre-drugand post-drug additions are used to determine the inhibitory effect ofeach compound. % inhibition of the peak control current during the27^(th) depolarization to +40 mV (in the 5 Hz train) is plotted as afunction of antagonist concentration. The concentrations of drugrequired to inhibit current by 50% (IC₅₀) are determined by fitting ofthe Hill equation to the concentration response data:% of Control=100×(1+([Drug]/IC₅₀)^(p))⁻¹

For each cell four arithmetic metrics are obtained:

-   -   1) seal resistance    -   2) baseline metric (the mean current at −70 mV from 5 to 45 ms        before the first depolarization to +40 mV)    -   3) current run up metric (pre-compound mean current amplitude        during the 1^(st) depolarization to +40 mV minus the        pre-compound mean current amplitude during the 27^(th)        depolarization to +40 mV)    -   4) peak current (maximum current amplitude during the 27^(th)        depolarization to +40 mV during the 5 Hz train).        All metrics are obtained during both the pre- and post-compound        addition traces. Cells are eliminated from further analysis if:    -   1) seal resistance is <50 MΩ    -   2) baseline metric is >±100 pA during the pre-compound    -   3) current run up metric is >−0.2 nA    -   4) pre-read peak metric is <400 pA.        The above-listed compounds provide ≧20% inhibition at a        concentration of 33 μM or less in the high throughput Kv1.5        planar patch clamp assay described above.        Atomic Absorption Spectroscopy Protocol:

This assay identifies agents that specifically block the human Kv1.5 K+channel heterologously expressed in CHO cells as measured by Rb⁺ effluxusing Flame Atomic Absorption Spectroscopy (FAAS). The application ofFAAS for measuring ion channel activity was adapted from Terstappen etal, Anal. Biochem., 272:149-155, 1999.

CHO cells expressing human Kv1.5 are cultured as described above, thenharvested with trypsin-EDTA and washed with medium.

-   -   1. 40,000 cells per well are seeded in a 96-well cell culture        plate (assay plate) and the cells are allowed to grow for 48        hours at 37° C.    -   2. The medium is removed and 200 μl of Rb Load Buffer (Aurora        Biomed, Vancouver, BC) is added for 3 hours at 37° C. under 5%        CO₂.    -   3. The cells are washed 5 times with 200 μl Hank's Balanced Salt        Solution (HBSS) followed by the addition of 100 μl HBSS        containing test compound or 0.5% DMSO.    -   4. After 10 min, 100 μl of HEPES-buffered saline containing 140        mM KCl is added and plate is incubated at RT for 5 min. with        gentle shaking.    -   5. Immediately thereafter, 150 μl of supernatant is transferred        to a fresh 96 well plate and the remaining supernatant        aspirated.    -   6. 120 μl of Cell Lysis Buffer (Aurora Biomed, Vancouver, BC) is        added to the assay plate and shaken for 10 min. prior to        analysis.    -   7. Rb content is measured in samples of supernatant (SUP) and        lysate (LYS) using an ICR-8000 automated AAS instrument (Aurora        Biomed, Vancouver, BC). % FLUX=100%*(SUP/(LYS+SUP)). %        INH=100%*(1−(A−B)/(C−B)), where A is % FLUX in the presence of        tested compound, B is % FLUX in the presence of 10 mM        (6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)-N,N-dimethylmethanaminium        chloride, C is % FLUX in the presence of 0.25% DMSO.

The above-listed compounds provide ≧25% inhibition at a concentration of25 μM or less in the AAS assay described above.

The compounds of this invention can be administered for the treatment orprevention of afflictions, diseases and illnesses according to theinvention by any means that effects contact of the active ingredientcompound with the site of action in the body of a warm-blooded animal.For example, administration, can be oral, topical, includingtransdermal, ocular, buccal, intranasal, inhalation, intravaginal,rectal, intracisternal and parenteral. The term “parenteral” as usedherein refers to modes of administration which include subcutaneous,intravenous, intramuscular, intraarticular injection or infusion,intrasternal and intraperitoneal.

The compounds can be administered by any conventional means availablefor use in conjunction with pharmaceuticals, either as individualtherapeutic agents or in a combination of therapeutic agents. They canbe administered alone, but are generally administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

For the purpose of this disclosure, a warm-blooded animal is a member ofthe animal kingdom possessed of a homeostatic mechanism and includesmammals and birds.

The dosage administered will be dependent on the age, health and weightof the recipient, the extent of disease, kind of concurrent treatment,if any, frequency of treatment and the nature of the effect desired.Usually, a daily dosage of active ingredient compound will be from about1-500 milligrams per day. Ordinarily, from 10 to 100 milligrams per dayin one or more applications is effective to obtain desired results.These dosages are the effective amounts for the treatment and preventionof afflictions, diseases and illnesses described above, e.g., cardiacarrhythmias such as atrial fibrillation, atrial flutter, atrialarrhythmia, and supraventricular tachycardia, thromboembolic events suchas stroke and congestive heart failure, and immunodepression.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, troches, dragées, granules and powders, or inliquid dosage forms, such as elixirs, syrups, emulsions, dispersions,and suspensions. The active ingredient can also be administeredparenterally, in sterile liquid dosage forms, such as dispersions,suspensions or solutions. Other dosages forms that can also be used toadminister the active ingredient as an ointment, cream, drops,transdermal patch or powder for topical administration, as an ophthalmicsolution or suspension formation, i.e., eye drops, for ocularadministration, as an aerosol spray or powder composition for inhalationor intranasal administration, or as a cream, ointment, spray orsuppository for rectal or vaginal administration.

Gelatin capsules contain the active ingredient and powdered carriers,such as lactose, starch, cellulose derivatives, magnesium stearate,stearic acid, and the like. Similar diluents can be used to makecompressed tablets. Both tablets and capsules can be manufactured assustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene gycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propylparaben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, A. Osol, a standard reference text in thisfield.

For administration by inhalation, the compounds of the present inventionmay be conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or nebulisers. The compounds mayalso be delivered as powders which may be formulated and the powdercomposition may be inhaled with the aid of an insufflation powderinhaler device. The preferred delivery system for inhalation is ametered dose inhalation (MDI) aerosol, which may be formulated as asuspension or solution of a compound of Formula I in suitablepropellants, such as fluorocarbons or hydrocarbons.

For ocular administration, an ophthalmic preparation may be formulatedwith an appropriate weight percent solution or suspension of thecompounds of Formula I in an appropriate ophthalmic vehicle, such thatthe compound is maintained in contact with the ocular surface for asufficient time period to allow the compound to penetrate the cornealand internal regions of the eye.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention include, but are not limited to, hard and soft gelatincapsules, tablets, parenteral injectables, and oral suspensions.

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules arewashed and dried.

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 100 milligrams of active ingredient, 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 275 milligrams of microcrystalline cellulose, 11 milligrams ofstarch and 98.8 milligrams of lactose. Appropriate coatings may beapplied to increase palatability or delay absorption.

A parenteral composition suitable for administration by injection isprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol. The solution is made to volume with water forinjection and sterilized.

An aqueous suspension is prepared for oral administration so that each 5milliliters contain 100 milligrams of finely divided active ingredient,100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodiumbenzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 millilitersof vanillin.

The same dosage forms can generally be used when the compounds of thisinvention are administered stepwise or in conjunction with anothertherapeutic agent. When drugs are administered in physical combination,the dosage form and administration route should be selected depending onthe compatibility of the combined drugs. Thus the term coadministrationis understood to include the administration of the two agentsconcomitantly or sequentially, or alternatively as a fixed dosecombination of the two active components.

Compounds of the invention can be administered as the sole activeingredient or in combination with a second active ingredient, includingother antiarrhythmic agents having Kv1.5 blocking activities such asquinidine, propafenone, ambasilide, amiodarone, flecainide, sotalol,bretylium, dofetilide, almokalant, bepridil, clofilium, other compoundshaving Kv1.5 blocking activities such as clotrimazole, ketoconazole,bupivacaine, erythromycin, verapamil, nifedipine, zatebradine,bisindolylmaleimide, or other cardiovascular agents such as, but notlimited to, ACE inhibitors such as benazepril, captopril, enalapril,fosinopril, lisinopril, moexipril, perindopril erbumine, quinapril,ramipril, and trandolapril, angiotensin II antagonists such ascandesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan,and valsartan, cardiac glycosides such as digoxin, L-type calciumchannel blockers, T-type calcium channel blockers, selective andnonselective beta blockers, an immunosuppresant compound, endothelinantagonists, thrombin inhibitors, aspirin, nonselective NSAIDs otherthan aspirin such as naproxen, warfarin, factor Xa inhibitors, lowmolecular weight heparin, unfractionated heparin, clopidogrel,ticlopidine, IIb/IIIa receptor antagonists such as tirofiban, 5HTreceptor antagonists, integrin receptor antagonists, thromboxanereceptor antagonists, TAFI inhibitors and P2T receptor antagonists.Compounds of the invention can also be administered as the sole activeingredient or in combination with a pacemaker or defibrillator device.

1. A compound of the structure:

or a pharmaceutically acceptable salt, crystal form, or hydrate,wherein: A is a) an aryl ring, wherein any stable aryl ring atom isindependently unsubstituted or substituted with 1) halogen, 2) NO₂, 3)CN, 4) CR⁴⁶═C(R⁴⁷R⁴⁸)₂, 5) C≡C R⁴⁶, 6) (CR^(i)R^(j))_(r)OR⁴⁶, 7)(CR^(i)R^(j))_(r)N(R⁴⁶R⁴⁷), 8) (CR^(i)R^(j))_(r)C(O)R⁴⁶, 9)(CR^(i)R^(j))_(r)C(O)R⁴⁶, 10) (CR^(i)R^(j))_(r)R⁴⁶, 11)(CR^(i)R^(j))_(r)S(O)₀₋₂R⁶¹, 12) (CR^(i)R^(j))_(r)S(O)₀₋₂N(R⁴⁶R⁴⁷), 13)OS(O)₀₋₂R⁶¹, 14) N(R⁴⁶)C(O)R⁴⁷, 15) N(R⁴⁶)S(O)₀₋₂R⁶¹, 16)(CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹, 17) (CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹OR⁴⁷, 18)(CR^(i)R^(j))_(r)N(R⁴⁶)(CR^(k)R^(l))_(s)C(O)N(R⁴⁷R⁴⁸), 19)N(R⁴⁶)(CR^(i)R^(j))_(r)R⁶¹, 20) N(R⁴⁶)(CR^(i)R^(j))_(r)N(R⁴⁷R⁴⁸), 21)(CR^(i)R^(j))_(r)C(O)N(R⁴⁷R⁴⁸), or 22) oxo, or b) a heteroaryl ringselected from the group consisting of a 5-membered unsaturatedmonocyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected fromthe group consisting or N, O or S, a 6-membered unsaturated monocyclicring with 1, 2, 3 or 4 heteroatom ring atoms selected from the groupconsisting N, O and S, and a 9- or 10-membered unsaturated bicyclic ringwith 1, 2, 3 or 4 heteroatom ring atoms selected from the groupconsisting or N, O or S; wherein any stable S heteroaryl ring atom isunsubstituted or mono- or di-substituted with oxo, and any stable C or Nheteroaryl ring atom is independently unsubstituted or substitutedwith 1) halogen, 2) NO₂, 3) CN, 4) CR⁴⁶═C(R⁴⁷R⁴⁸)₂, 5) C≡CR⁴⁶, 6)(CR^(i)R^(j))_(r)OR⁴⁶, 7) (CR^(i)R^(j))_(r)N(R⁴⁶R⁴⁷), 8)(CR^(i)R^(j))_(r)C(O)R⁴⁶, 9) (CR^(i)R^(j))_(r)C(O)OR⁴⁶, 10)(CR^(i)R^(j))_(r)R⁴⁶, 11) (CR^(i)R^(j))_(r)S(O)₀₋₂R⁶¹, 12)(CR^(i)R^(j))_(r)S(O)O₀₋₂N(R⁴⁶R⁴⁷), 13) OS(O)₀₋₂R⁶¹, 14) N(R⁴⁶)C(O)R⁴⁷,15) N(R⁴⁶)S(O)₀₋₂R⁶¹, 16) (CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹, 17)(CR^(i)R^(j))_(r)N(R⁴⁶)R⁶¹OR⁴⁷, 18)(CR^(i)R^(j))_(r)N(R⁴⁶)(CR^(k)R^(l))_(s)C(O)N(R⁴⁷R⁴⁸), 19)N(R⁴⁶)(CR^(i)R^(j))_(r)R⁶¹, 20) N(R⁴⁶)(CR^(i)R^(j))_(r)N(R⁴⁷R⁴⁸), 21)(CR^(i)R^(j))_(r)C(O)N(R⁴⁷R⁴⁸), or 22) oxo; R¹ is selected from thegroup consisting of 1) hydrogen, 2) (CR^(a)R^(b))_(n)R⁴⁰ 3)(CR^(a)R^(b))_(n)R⁴⁰, 4) (CR^(a)R^(b))_(n)N(R⁴⁰R⁴¹), 5)(CR^(a)R^(b))_(n)N(R⁴⁰)C(O)OR⁴¹, 7) C₃₋₈ cycloalkyl, 8)(CR^(a)R^(b))_(n)C(O)OR⁴⁰, 9)(CR^(a)R^(b))_(n)N(R⁴⁰)(CR^(c)R^(d))₁₋₃R⁴¹, 10)(CR^(a)R^(b))_(n)S(O)₀₋₂R⁶, 11) (CR^(a)R^(b))_(n)S(O)₀₋₂N(R⁴⁰R⁴¹), 12)(CR^(a)R^(b))_(n)N(R⁴⁰)R⁶OR⁴¹, 13)(CR^(a)R^(b))_(n)N(R⁴⁰)(CR^(c)R^(d))₀₋₆C(O)N(R⁴¹R⁴²); R², R⁸, R⁹ and R¹⁰are independently selected from: 1) hydrogen, 2) halogen, 3) NO₂, 4) CN,5) CR⁴³═C(R⁴⁴R⁴⁵), 6) C≡CR⁴³, 7) (CR^(e)R^(f))_(p)OR⁴³, 8)(CR^(e)R^(f))_(p)N(R⁴³R⁴⁴), 9) (CR^(e)R^(f))_(p)C(O)R⁴³, 10)(CR^(e)R^(f))_(p)C(O)OR⁴³, 11) (CR^(e)R^(f))_(p)R⁴³, 12)(CR^(e)R^(f))_(p)S(O)₀₋₂R⁶⁰, 13) (CR^(e)R^(f))_(p)S(O)₀₋₂R⁴³R⁴⁴, 14)OS(O)₀₋₂R⁶⁰, 15) N(R⁴³)C(O)R⁴⁴, 16) N(R⁴³)S(O)₀₋₂R⁶⁰, 17)(CR^(e)R^(f))_(p)N(R⁴³)R⁶⁰, 18) (CR^(e)R^(f))_(p)N(R⁴³)R⁶⁰OR⁴⁴, 19)(CR^(e)R^(f))_(p)N(R⁴³)(CR^(g)R^(h))_(q)C(O)N(R⁴⁴R⁴⁵), 20)N(R⁴³)(CR^(e)R^(f))_(p)R⁶⁰, 21) N(R⁴³)(CR^(e)R^(f))_(p)N(R⁴⁴R⁴⁵), and22) (CR^(e)R^(f))_(p)C(O)N(R⁴³R⁴⁴), or R² and R⁸ are independently asdefined above, and R⁹ and R¹⁰, together with the atoms to which they areattached, form the ring

where R^(m) is C₁₋₆alkyl; R^(a), R^(b), R^(c), R^(d), R^(e), R^(f),R^(g), R^(h), R^(i), R^(j), R^(k), and R^(l) are independently selectedfrom the group consisting of: 1) hydrogen, 2) C₁-C₆ alkyl, 3) halogen,4) aryl, 5) R⁸⁰, 6) C₃-C₁₀ cycloalkyl, and 7) OR⁴, said alkyl, aryl, andcycloalkyl being unsubstituted, monosubstituted with R⁷, disubstitutedwith R⁷ and R¹⁵, trisubstituted with R⁷, R¹⁵ and R¹⁶, ortetrasubstituted with R⁷, R¹⁵, R¹⁶ and R¹⁷; R⁴, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴,R⁴⁵, R⁴⁶, R⁴⁷, R⁴⁸, R⁴⁹, R⁵¹, R⁵², R⁵³ and R⁵⁴ are independentlyselected from the group consisting of 1) hydrogen, 2) C₁-C₆ alkyl, 3)C₃-C₁₀cycloalkyl, 4) aryl, 5) R⁸¹, 6) CF₃, 7) C₂-C₆alkenyl, and 8) C₂-C₆alkynyl, said alkyl, aryl, and cycloalkyl is unsubstituted,mono-substituted with R¹⁸, di-substituted with R¹⁸ and R¹⁹,tri-substituted with R¹⁸, R¹⁹ and R²⁰, or tetra-substituted with R¹⁸,R¹⁹, R²⁰ and R²¹; R⁶, R⁶⁰, R⁶¹, and R⁶³ are independently selected fromthe group consisting of 1) C₁-C₆ alkyl, 2) aryl, 3) R⁸³, and 4) C₃-C₁₀cycloalkyl; said alkyl, aryl, and cycloalkyl is unsubstituted,mono-substituted with R²⁶, di-substituted with R²⁶ and R²⁷,tri-substituted with R²⁶, R²⁷ and R²⁸, or tetra-substituted with R²⁶,R²⁷, R²⁸ and R²⁹; R⁷, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²⁶, R²⁷, R²⁸,and R²⁹ are independently selected from the group consisting of 1) C₁-C₆alkyl, 2) halogen, 3) OR⁵¹, 4) CF₃, 5) aryl, 6) C₃-C₁₀cylcoalkyl, 7)R⁸⁴, 8) S(O)₀₋₂N(R⁵¹R⁵²), 9) C(O)OR⁵¹, 10) C(O)R⁵¹, 11) CN, 12)C(O)N(R⁵¹R⁵²), 13) N(R⁵¹)C(O)R⁵², 14) S(O)₀₋₂R⁶³, 15) NO₂, 16)N(R⁵¹R⁵²), and 17) R⁸²; R²² selected from the group consisting of 1)NHC(O)R⁸⁸, and 2) N(R⁵³R⁵⁴); R⁸⁸ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl;R⁸⁰, R⁸¹, R⁸², R⁸³, R⁸⁴ and R⁸⁵ are independently selected from a groupof unsubstituted or substituted heterocyclic rings consisting of a 3-6membered unsaturated or saturated monocyclic ring with 1, 2, or 3heteroatom ring atoms selected from the group consisting N, O and S, anda 9- or 10-membered unsaturated or saturated bicyclic ring with 1, 2, 3or 4 heteroatom ring atoms selected from the group consisting or N, O orS; and n, p, g, r, and s are independently 0, 1, 2, 3, 4, 5 or 6,wherein R⁵ is selected from the group consisting of —(CH₂)₂NH₂,—(CH₂)₂NHC(O)CH₃, —(CH₂)₂N(CH₂CH₃)₂,


2. A compound of claim 1, or a pharmaceutically acceptable salt thereof,selected from the group consisting of3-(2-Aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one,N-[2-(6-Methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]acetamide,6-Methoxy-2-methyl-4-phenyl-3-(2-piperidin-1-ylethyl)isoquinolin-1(2H)-one,6-Methoxy-2-methyl-3-[2-(2-oxopyrrolidin-1-yl)ethyl]-4-phenylisoquinolin-1(2H)-one,6-Methoxy-2-methyl-3-(2-morpholin-4-ylethyl)-4-phenylisoquinolin-1(2H)-one,3-[2-(Diethylamino)ethyl]-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one,N-[2-(6-Methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]-1-(4-methoxyphenyl)cyclopropanecarboxamide,1-Cyano-N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]cyclopropanecarboxamide,N-[2-(6-Methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]-1-(4-methoxyphenyl)acetamide,1-(2,4-Dichlorophenyl)-N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]cyclopropanecarboxamide,N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]-1-phenylcyclopropanecarboxamide,tert-Butyl1-({[[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]amino}carbonyl)cyclopropylcarbamate,1-Amino-N-[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]cyclopropanecarboxamide,4-Methoxy-N-[1-({[2-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl]amino}carbonyl)cyclopropyl]benzamide,(±)-Benzyl3-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)piperidine-1-carboxylate,(±)-6-Methoxy-2-methyl-4-phenyl-3-piperidin-3-ylisoquinolin-1(2H)-one,(±)-3-(1-Acetylpiperidin-3-yl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one,3-(1-acetylpiperidin-4-yl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one,6-methoxy-2-methyl-3-[1-(methylsulfonyl)piperidin-4-yl]-4-phenylisoquinolin-1(2H)-one,(±)-6-Methoxy-2-methyl-3-[1-(methylsulfonyl)piperidin-3-yl]-4-phenylisoquinolin-1(2H)-one,(±)-3-(1-Benzoylpiperidin-3-yl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one3-(Pyrid-2-yl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one, and3-(Thiazol-2-yl)-6-methoxy-2-cyclopropyl-4-phenylisoquinolin-1(2H)-one.3. A method of treating a condition in a mammal, the treatment of whichis effected or facilitated by K_(v)1.5 inhibition, which comprisesadministering a compound of claim 1 in an amount that is effective atinhibiting K_(v)1.5 wherein the condition is cardiac arrhythmia.
 4. Amethod of claim 3, wherein the cardiac arrythmia is atrial fibrillation.5. A method of claim 3, wherein the cardiac arrythmia is selected fromthe group consisting of atrial flutter, atrial arrhythmia andsupraventricular tachycardia.
 6. A pharmaceutical formulation comprisinga pharmaceutically acceptable carrier and the compound claim 1 or apharmaceutically acceptable crystal form or hydrate thereof.
 7. Apharmaceutical composition made by combining the compound of claim 1 anda pharmaceutically acceptable carrier.
 8. A method of treating cardiacarrythmia comprising administering a compound of claim 1 with a compoundselected from one of the classes of compounds consisting ofantiarrhythmic agents having Kv1.5 blocking activities, ACE inhibitors,angiotensin II antagonists, cardiac glycosides, L-type calcium channelblockers, L-type calcium channel blockers, selective and nonselectivebeta blockers, endothelin antagonists, thrombin inhibitors, aspirin,nonselective NSAIDs, warfarin, factor Xa inhibitors, low molecularweight heparin, unfractionated heparin, clopidogrel, ticlopidine,IIb/IIIa receptor antagonists, 5HT receptor antagonists, integrinreceptor antagonists, thromboxane receptor antagonists, TAFI inhibitorsand P2T receptor antagonists.
 9. A method for treating tachycardia in apatient which comprises treating the patient with an antitachycardiadevice in combination with a compound of claim 1.